The Hummingbirds' Foundation for M.E. (HFME) is fighting for the recognition of M.E.,
and for patients to be accorded the same basic human rights as those with similar
disabling and potentially fatal neurological diseases such as M.S.

An important note:

Before reading the research/advocacy information given in the links below, please be aware of the following facts:

1.Myalgic Encephalomyelitis and ‘Chronic Fatigue Syndrome’ are not synonymous terms. The overwhelming majority of research on ‘CFS’ or ‘CFIDS’ or ‘ME/CFS’ or ‘CFS/ME’ or ‘ICD-CFS’ does not involve M.E. patients and is not relevant in any way to M.E. patients. If the M.E. community were to reject all ‘CFS’ labelled research as ‘only relating to ‘CFS’ patients’ (including research which describes those abnormalities/characteristics unique to M.E. patients), however, this would seem to support the myth that ‘CFS’ is just a ‘watered down’ definition of M.E. and that M.E. and ‘CFS’ are virtually the same thing and share many characteristics.

A very small number of ‘CFS’ studies refer in part to people with M.E. but it may not always be clear which parts refer to M.E. The A warning on ‘CFS’ and ‘ME/CFS’ research and advocacypaper is recommended reading and includes a checklist to help readers assess the relevance of individual ‘CFS’ studies to M.E. (if any) and explains some of the problems with this heterogeneous and skewed research.

In future, it is essential that M.E. research again be conducted using only M.E. defined patients and using only the term M.E. The bogus, financially-motivated disease category of ‘CFS’ must be abandoned.

2. The research referred to on this website varies considerably in quality. Some is of a high scientific standard and relates wholly to M.E. and uses the correct terminology. Other studies are included which may only have partial or minor possible relevance to M.E., use unscientific terms/concepts such as ‘CFS,’ ‘ME/CFS,’ ‘CFS/ME,’ ‘CFIDS’ or Myalgic ‘Encephalopathy’ and also include a significant amount of misinformation. Before reading this research it is also essential that the reader be aware of the most commonly used ‘CFS’ propaganda, as explained in A warning on ‘CFS’ and ‘ME/CFS’ research and advocacyand in more detail in Putting research and articles on Myalgic Encephalomyelitis into context.

Miscellaneous research

Abstract: Several different meanings have been attached to the term "chemical sensitivity" by those who use it. Feeling ill from odors is a symptom reported by approximately one-third of the population. The syndrome of chemical sensitivity, frequently called "Multiple Chemical Sensitivity" or "MCS" has been the subject of three federally-sponsored workshops; at least five different case definitions for research on MCS have been proposed. In contrast, the hypothesis that chemical sensitivity may be a mechanism for disease posits that a broad spectrum of "recognized" chronic illnesses, ranging from asthma and migraine to depression and chronic fatigue, may be the consequence of environmental chemical exposures. According to this theory, a two-step process occurs: (1) an initial salient exposure event(s) (for example, a one-time, intermittent, or continuous exposure to pesticides, solvents, or air contaminants in a sick building) interacts with a susceptible individual, causing loss of tolerance for everyday, low level chemical inhalants (car exhaust, fragrances, cleaning agents), as well as for foods, drugs, alcohol, and caffeine; (2) thereafter, such common, formerly well-tolerated substances trigger symptoms, thus perpetuating illness. "Masking" (acclimatization, apposition, and addiction) may hide these exposure-symptom relationships, thus obfuscating the environmental etiology of the illness. Accumulating clinical observations lend credence to a view of chemical sensitivity as an emerging theory of disease causation and underscore the need for its testing in a rational, scientific manner. While chemical sensitivity may be the consequence of chemical exposure, the term "toxicant-induced loss of tolerance" more fully describes the two-step process under scrutiny.

Abstract: The purpose of the study was to search for a means of diminishing the plight of patients with chronic fatigue syndrome (CFS) and to test the hypothesis that central to the pathogenesis of CFS is a cholinergic defect. Forty-nine patients who fulfilled consensus criteria for CFS were treated with the acetylcholinesterase inhibitor, galanthamine hydrobromide. Thirtynine patients finsihed the study according to the protocol with 43% reporting 50% improvement whereas patients in the placebo group reported only 10% improvement in the same parameters of CFS. The improvement of patients on galanthamine was in most cases gradual and reached significance for the group only after four to eight weeks. The improvement was stable, and no patients who reported over 50% improvement on galanthamine relapsed to a pretrial level of any symptom. One of the most surprising effects was the dramatic improvement of sleep disturbances that occurred in most patients on this medication: more than 60% of the patients who finished the study reported over 70% improvement in sleep deficit. If the subjective report by patients can be proved by objective means, this would be the first demonstration of a drug that can be used to correct a sleep disturbance that also influences a specific stage in normal sleep. The most common adverse effect of galanthamine, as given in this study, was nausea that was dose-dependent and reversible. Galanthamine hydrobromide is relatively safe and appears to be an effective medication against many symptoms of CFS. But the positive results of this study have to be interpreted cautiously because of methodological limitations of this trial. First, this study was originally organized as a double-blind, placebo-controlled trial but was changed to an optional crossover after two weeks of treatment. Also, the adverse effects of the active drug in 30% of patients could compromise the double-blind. With these limitations in mind, it is nevertheless tempting to conclude that this study lends an indirect support to our hypothesis that a cholinergic deficit may play a role in the pathogenesis of the syndrome.

Abstract: Sixty-three adults with the diagnosis of the postviral fatigue syndrome were enrolled in a double-blind, placebo-controlled study of essential fatty acid therapy. The patients had been ill for from one to three years after an apparently viral infection, suffering from severe fatigue, myalgia and a variety of psychiatric symptoms. The preparation given contained linoleic, gamma-linolenic, eicosapentaenoic and docosahexaenoic acids and either it, or the placebo, was given as 8 x 500 mg capsules per day over a 3-month period. The trial was parallel in design and patients were evaluated at entry, one month and three months. In consultation with the patient the doctors assessed overall condition, fatigue, myalgia, dizziness, poor concentration and depression on a 3-point scale. The essential fatty acid composition of their red cell membrane phospholipids was analysed at the first and last visits. At 1 month, 74% of patients on active treatment and 23% of those on placebo assessed themselves as improved over the baseline, with the improvement being much greater in the former. At 3 months the corresponding figures were 85% and 17% (p less than 0.0001) since the placebo group had reverted towards the baseline state while those in the active group showed continued improvement. The essential fatty acid levels were abnormal at the baseline and corrected by active treatment. There were no adverse events. We conclude that essential fatty acids provide a rational, safe and effective treatment for patients with the post-viral fatigue syndrome.

Abstract: Several conventional claims regarding Gulf War Syndrome are criticized: that Gulf War veterans are no sicker than the civilian population as a whole; that Gulf War Syndrome is a myth invented by the press; that GWS cannot be defined as a legitimate medical syndrome; that since its cause cannot be determined, it is not a problem associated with Operation 'Desert Storm'; that the US and UK governments are doing all they can to investigate and treat illness in veterans or deny existence of over 100,000 cases in veterans and their families; that GWS will settle without treatment; that the armed forces were well prepared for integrated conflict involving chemical and biological warfare in the Middle East, increasing the risk of this in the future.

Abstract: PURPOSE: To study the reliability of a serum angiotensin-converting enzyme (ACE) assay as a marker for the chronic fatigue-immune dysfunction syndrome (CFIDS), and to compare some enzyme characteristics of ACE in CFIDS with that in sarcoidosis. PATIENTS AND METHODS: Forty-nine patients with CFIDS and 56 endemic control subjects from Lyndonville, New York, and Charlotte, North Carolina; plus 23 untreated patients with active sarcoidosis, 24 with sarcoidosis receiving corticosteroid therapy, and 32 patient controls without sarcoidosis from California. Serum ACE levels were determined with a spectrophotometric method. The effect of freezing and thawing and the effect of storage at 4 degrees C were compared between CFIDS and sarcoidosis samples. RESULTS: Serum ACE levels were elevated in 80% of patients with CFIDS and 30% of endemic control subjects as compared with 9.4% of nonendemic California control subjects. The ACE activity in CFIDS differed from that in sarcoidosis because of its lability with storage at 4 degrees C in CFIDS and its partial activation with freezing and thawing. Thus, ACE activity was elevated in the majority of CFIDS patients either upon initial assay or upon a subsequent assay after refreezing. ACE activity was elevated in 87% of patients with active sarcoidosis and was not affected by storage or freezing and thawing. CONCLUSIONS: Serum ACE elevations may be a useful marker for CFIDS, especially if a method can be developed to distinguish ACE in CFIDS from that in sarcoidosis. The sensitivity for CFIDS was 80%, with 68% specificity in an endemic area. The increased prevalence of serum ACE elevations in endemic controls as compared with nonendemic controls suggests that an ACE increase may be an early manifestation of CFIDS and supports the concept that CFIDS is a definite disease state.

Abstract: The chronic fatigue syndrome is poorly understood. We believe the underlying causes in many atopics and women are a persistent infection and hypersensitivity to the immune-suppressive effects of histamine and certain pathogens. We believe much of the symptomatology can be explained by all four types of hypersensitivity (Gell and Coombs classification) in reaction to a pathogen, electrolyte disturbances which include sometimes permanent changes in cell membranes' ability to pass electrolytes, sometimes permanent biochemical changes in mitochondrial function, and disturbances of insulin and T3-thyroid hormone functions. We also explain in detail what 'fatigue' means for these patients. We present evidence from the medical literature for the plausibility of our hypotheses.

Abstract: Sixty-three adults with the diagnosis of the postviral fatigue syndrome were enrolled in a double-blind, placebo-controlled study of essential fatty acid therapy. The patients had been ill for from one to three years after an apparently viral infection, suffering from severe fatigue, myalgia and a variety of psychiatric symptoms. The preparation given contained linoleic, gamma-linolenic, eicosapentaenoic and docosahexaenoic acids and either it, or the placebo, was given as 8 x 500 mg capsules per day over a 3-month period. The trial was parallel in design and patients were evaluated at entry, one month and three months. In consultation with the patient the doctors assessed overall condition, fatigue, myalgia, dizziness, poor concentration and depression on a 3-point scale. The essential fatty acid composition of their red cell membrane phospholipids was analysed at the first and last visits. At 1 month, 74% of patients on active treatment and 23% of those on placebo assessed themselves as improved over the baseline, with the improvement being much greater in the former. At 3 months the corresponding figures were 85% and 17% (p less than 0.0001) since the placebo group had reverted towards the baseline state while those in the active group showed continued improvement. The essential fatty acid levels were abnormal at the baseline and corrected by active treatment. There were no adverse events. We conclude that essential fatty acids provide a rational, safe and effective treatment for patients with the post-viral fatigue syndrome.

Abstract: Because estimates of the prevalence of Chronic Fatigue Syndrome (CFS) have been quite variable, there is a need for a screening instrument and second stage medical assessment that will produce the most valid estimate of the CFS prevalence. In the present study, four groups of 15 subjects each were recruited: patients diagnosed with (1) CFS, (2) Lupus, (3) Multiple Sclerosis (MS), and (4) a healthy control group. Participants were interviewed twice over a two week period of time with a screening instrument comprising The Fatigue Scale and a newly configured section. The screening instrument had excellent test-retest and interrater reliability. This screening instrument therefore has utility for CFS community-based epidemiologic research. However, while the instrument differentiates patients with CFS from those who are healthy, it is less likely to distinguish CFS from other autoimmune diseases (especially Lupus). Thus, future community-based CFS prevalence studies whould encompass both a screening and a medical examination to adequately differentiate CFS from other illnesses with overlapping symptomatology. We recommend a two-stage research design with (1) a screening instrument with good sensitivity and (2) medical assessments of CFS positives from stage 1 to deal with the specificity problem.

Abstract: Chronic fatigue syndrome (CFS) has been increasingly associated with immune dysregulation, including depressed natural killer cell activity; this phenomenon is associated with increased susceptibility to cancer. Although anecdotal reports have suggested an association between CFS and cancer, particularly non-Hodgkin's lymphoma and brain cancer, there has been no a priori justification for evaluating such an association and no consideration of relevant parameters, such as length of latent period vs. tumor type. We reviewed data from the Nevada State Cancer Registry subsequent to a reported outbreak of a CFS-like illness in Nevada that occurred during 1984-1986. We concentrated on non-Hodgkin's lymphoma and brain/CNS tumors, with particular emphasis on persons 15-34 and 35-54 years of age. An upward trend in the incidence of brain/CNS tumors, which could be related to a national upward trend for this disease, was noted. No consistent trends were noted for non-Hodgkin's lymphoma. Because of the difficulties inherent in studies of cancer subsequent to various exposures, we evaluated the methodology for determining an association between outbreaks of CFS-like disease and cancer. We propose several approaches that should be considered in future studies for investigation of possible associations between CFS and cancer, including expected latent periods for specific tumors.

Abstract: We studied the economic impact of chronic fatigue syndrome (CFS) on the individual, the government, and the community by calculating the direct and indirect costs related to this disorder in the Richmond Vally, a circumscribed semiurban population in northern New South Wales. Data were collected from cases identified in our previous prevalence study in this region; these cases provided the basis for the current data collection (1). Data regarding utilization of health care resources, income, and employment were obtained from patients by questionnaire. In addition, aggregate data from Medicare (the universal health care organization) on the incidence of and the fees charged for each schedule item for the patients in our survey were obtained. The conservative estimate of the per annum cost of CFS in the Richmond Valley, with a prevalence of 37.1 cases per 100,000 population, was $396,000. Direct medical costs of ~$2000 per patient per annum were recorded. If extrapolated to the entire population of Australia, we estimate that CFS would account for annual costs of at least $59 million. CFS accounts for a large but neglected area of health care resource utilization and imposes a significant economic burden. Reference: Lloyd AR, Hickie I, Boughton CR, Spencer O, Wakefield D. The prevalence of chronic fatigue syndrome in an Australian population.

BACKGROUND: In this study we tested the hypothesis that the increased sensitivity to glucocorticoids in chronic fatigue syndrome (CFS)-patients can be attributed to an altered functioning of their glucocorticoid receptors (GR). METHODS: For this purpose, affinity and distribution of the GR were studied in purified, peripheral blood mononuclear cells (PBMC) of 10 CFS patients and 14 controls along with the responsiveness of these cells to glucocorticoids in vitro. RESULTS: Affinity (Kd) and number of GR was not different in PBMC of CFS patients when compared with the controls (Kd, 12.9 +/- 8.9 nmol vs 18.8 +/- 16.2 nmol and GR number, 4,839 +/- 2,824/ cell vs 4,906 +/- 1,646/cell). Moreover, RT-PCR revealed no differences in GR messenger RNA expression. Nevertheless, PBMC from CFS patients showed an increased sensitivity to glucocorticoids in vitro. In CFS patients 0.01 micromol dexamethasone suppressed PBMC proliferation by 37%, whereas the controls were only suppressed by 17% (P < 0.01). Addition of phorbol 12-myristate 13-acetate to the cultures rendered the cells resistant to dexamethasone with regard to proliferation and IL-10 and IFN-gamma production, but not to IL-2 and TNF-alpha production in both patients and controls. No difference between patients and controls was observed in this respect CONCLUSIONS: In conclusion, PBMC of CFS patients display an increased sensitivity to glucocorticoids, which cannot be explained by number or affinity of the GR but should rather be attributed to molecular processes beyond the actual binding of the ligand to the GR.

Abstract Gastrointestinal symptoms are common in patients with Chronic Fatigue Syndrome (CFS). The objective of this study was to determine the frequency of these symptoms and explore their relationship with objective (radionuclide) studies of upper GI function.Methods

The questionnaires showed a significant difference in gastric (p>0.01) symptoms and swallowing difficulty. Nocturnal diarrhoea was a significant symptom not previously reported. 5/32 CFS subjects showed slightly delayed oesophageal clearance, but overall there was no significant difference from the control subjects, nor correlation of oesophageal clearance with symptoms. 23/32 patients showed a delay in liquid gastric emptying, and 12/32 a delay in solid gastric emptying with the delay significantly correlated with the mean symptom score (for each p<<0.001).\

Serine is an important precursor of tryptophan and serotonin. Previous studies of patients with chronic fatigue syndrome (CFS) demonstrated that serine (CFSUM2) was an important urinary metabolite discriminating between CFS from control subjects, and was negatively correlated with CFS neurological symptom index and total symptom index. Serine synthesis requires both alanine and glycine as precursors, and also as a result of microbial metabolism. The aim of this study is to determine if faecal microorganisms can produce serine, and how these organisms are quantitatively related to the total gastrointestinal microbial flora in CFS patients.

Three clinical faecal coliforms (Escherichia coli, Enterobacter cloacae and Proteus mirabilis) were incubated in defined broth and their metabolites were analyzed by a gas chromatogram (GC-MS). Serine was produced by the three organisms at varying concentrations. Other amino acids including serine precursors (alaine & glycine), leucine, phenylalanine and succinic acid, an organic acid, were also detected suggesting that the contribution of microbial metabolites by enteric organisms to achieve a balanced diet may be more important as previously thought.

Faecal samples from 27 CFS patients and four age and sex matched control subjects were studied. Quantitative bacteriology was performed on all samples. Seventeen (62.9%) CFS patients had a low % distribution of E.coli (<80% of total aerobic faecal count). In contrast none all four control subjects had a low % distribution of E.coli ( p < 0.03).

These studies showed that the low urinary excretion of serine in CFS patients reported in previous study was associated with a disturbed gastrointestinal microbial flora. Alteration in the aerobic microbial flora, particularly the Gram negative enteric organisms, may change the exogenous supply of serine and contribute to the increased symptoms expression of patients with CFS.

Chronic fatigue syndrome (CFS) is a syndrome of uncertain etiopathogenesis characterized by disabling fatigue associated with a variable number of somatic and/or neuropsychologic symptoms. In patients with CFS, several immunologic abnormalities can be detected, including a higher prevalance of allergy. The aim of this study was to determine whether CFS patients, well studied for their allergy profile, show signs of eosinophil activation, as detectable by the measurement in serum of eosinophil cationic protein (ECP) levels. In 35 consecutive CFS outpatients (diagnosis based on the Centers for Disease Control case definition), ECP was measured in serum by a competitive enzyme immunoassay (ECP-FEIA kit, Kabi Pharmacia Diagnostics, Uppsala, Sweden). Fourteen disease-free subjects with no history of CFS or allergy were selected as controls. ECP serum levels were significantly higher in CFS patients than in controls (18.0 ± 11.3 micrograms/l vs 7.3 ± 2.1 micrograms/l; P <0.01). In the CFS population, the prevalence of RAST positivity to one or more allergens was 77%, while no control showed positive RAST. Twelve of the 14 CFS patients with increased ECP serum levels were RAST-positive. However, CFS RAST-positive patients had no significantly higher ECP serum levels than CFS RAST-negative patients (19.3 ± 12.4 micrograms/l vs 13.6 ± 3.7 micrograms/l; P="0.4)." This is the first report of increased serum levels of ECP in CFS. On the basis of the available data, it is discussed whether eosinophil activation has a pathogenetic role in CFS or is linked to the frequently associated allergic condition, or, finally, whether a common immunologic background may exist for both atopy and CFS.

Abstract: We determined the extent to which chronic fatigue syndrome (CFS) patients with sicca symptoms fulfil the diagnostic criteria for Sjogren's syndrome (SS). Three sets of diagnostic criteria for SS, formulated by the Japanese, Europeans and Fox, were used. One-third of the CFS patients with sicca symptoms fulfilled the diagnostic criteria for SS. However, they were 'seronegative', differing from the ordinary primary SS.

Abstract: Patients with chronic fatigue syndrome (CFS) often complain of an inability to maintain activity levels and a variety of autonomic-like symptoms that make everyday activity intolerable at times. The purpose of the study was to determine if there were differences in vagal activity at fixed breathing rates in women with CFS. Twelve women with the diagnosis of CFS between the ages of 32 and 59 years volunteered for the study. Healthy women, who were between the ages of 30 and 49, served as controls. Full signal electrocardiograph and respiratory signals were collected during a paced breathing protocol of three fixed breathing rates (8, 12 and 18 breaths/min) performed in the sitting and standing postures. Vagal activity was analyzed by means of heart rate spectral analysis to determine the subject's response to specific breathing rates and postures. Heart rate variability was used as a non-invasive method of measuring the parasympathetic component of the autonomic nervous system. Using this method, although there was significantly less vagal power in the sitting versus the standing postures for both groups, the overall vagal power was significantly lower (p < 0.034) in the CFS group versus healthy controls. Vagal power was also significantly lower (p < 0.01 to p < 0.05) at all breathing rates in both postures except while standing and breathing at 18 breaths/min. Knowledge of the differences in vagal activity for CFS patients may allow stratification for the analysis of other research variables.

Abstract: The hypothesis that patients with chronic fatigue syndrome (CFS) have low red blood cell magnesium and that magnesium treatment would improve the wellbeing of such patients were tested in a case-control study and a randomised, double-blind, placebo-controlled trial, respectively. In the case-control study, 20 patients with CFS had lower red cell magnesium concentrations than did 20 healthy control subjects matched for age, sex, and social class (difference 0.1 mmol/l, 95% confidence inteval [Cl] 0.05 to 0.15) In the clinical trial, 32 patients with CFS were randomly allocated wither to intramuscular magnesium sulphate every week for 6 weeks (15 patients) or to placebo (17). Patients treated with magnesium claimed to have improved energy levels, better emotional state, and less pain, as judged by changes in the Nottingham health profile. 12 of the 15 treated patients said they had benefited from treatment, and in 7 patients energy score improved from the maximum to the minimum. By contrast, 3 of the 17 patients said that they felt better (difference 62%, 95% CI 35 to 90), and 1 patient had a better energy score. Red cell magnesium returned to normal in all patients on magnesium but in only 1 patient on placebo. The findings show that magnesium may have a role in CFS.

Abstract: Carnitine is essential for mitochondrial energy production. Disturbance in mitochondrial function may contribute to or cause the fatigue seen in Chronic Fatigue Syndrome (CFS) patients. Previous investigations have reported decreased carnitine levels in CFS. Orally administered L-carnitine is an effective medicine in treating the fatigue seen in a number of chronic neurologic diseases. Amantadine is one of the most effective medicines for treating the fatigue seen in multiple sclerosis patients. Isolated reports suggest that it may also be effective in treating CFS patients. Formal investigations of the use of L-carnitine and amantadine for treating CFS have not been previously reported. We treated 30 CFS patients in a crossover design comparing L-carnitine and amantadine. Each medicine was given for 2 months, with a 2-week washout period between medicines. L-Carnitine or amantadine was alternately assigned as fist medicine. Amantadine was poorly tolerated by the CFS patients. Only 15 were able to complete 8 weeks of treatment, the others had to stop taking the medicine due to side effects. In those individuals who completed 8 weeks of treatment, there was no statistically significant difference in any of the clinical parameters that were followed. However, with L-carnitine we found statistically significant clinical improvement in 12 of the 18 studied parameters after 8 weeks of treatment. None of the clinical parameters showed any deterioration. The greatest improvement took place between 4 and 8 weeks of L-carnitine treatment. Only 1 patient was unable to complete 8 weeks of treatment due to diarrhea. L-Carnitine is a safe and very well tolerated medicine which improves the clinical status of CFS patients. In this study we also analyzed clinical and laboratory correlates of CFS symptomatology and improvement parameters.

Abstract: The purpose of the study was to search for a means of diminishing the plight of patients with chronic fatigue syndrome (CFS) and to test the hypothesis that central to the pathogenesis of CFS is a cholinergic defect. Forty-nine patients who fulfilled consensus criteria for CFS were treated with the acetylcholinesterase inhibitor, galanthamine hydrobromide. Thirtynine patients finsihed the study according to the protocol with 43% reporting 50% improvement whereas patients in the placebo group reported only 10% improvement in the same parameters of CFS. The improvement of patients on galanthamine was in most cases gradual and reached significance for the group only after four to eight weeks. The improvement was stable, and no patients who reported over 50% improvement on galanthamine relapsed to a pretrial level of any symptom. One of the most surprising effects was the dramatic improvement of sleep disturbances that occurred in most patients on this medication: more than 60% of the patients who finished the study reported over 70% improvement in sleep deficit. If the subjective report by patients can be proved by objective means, this would be the first demonstration of a drug that can be used to correct a sleep disturbance that also influences a specific stage in normal sleep. The most common adverse effect of galanthamine, as given in this study, was nausea that was dose-dependent and reversible. Galanthamine hydrobromide is relatively safe and appears to be an effective medication against many symptoms of CFS. But the positive results of this study have to be interpreted cautiously because of methodological limitations of this trial. First, this study was originally organized as a double-blind, placebo-controlled trial but was changed to an optional crossover after two weeks of treatment. Also, the adverse effects of the active drug in 30% of patients could compromise the double-blind. With these limitations in mind, it is nevertheless tempting to conclude that this study lends an indirect support to our hypothesis that a cholinergic deficit may play a role in the pathogenesis of the syndrome.

Abstract: Chronic fatigue syndrome (CFS) is characterized by unexplained, debilitating fatigue or easy fatigability lasting longer than six months. While a number of clinical trials have been performed in CFS patients, there is currently no established therapy for CFS. Treatment with acyclovir of CFS patients is ineffective. Intravenous immunoglobulin therapy appears to be effective, though the results are controversial. Antidepressants might help the associated depression and anxiety but not other symptoms. Trials with magnesium have improved the well-being of patients. Restoration of NK activity by biological response modifiers, such as sizofirann, resulted in restoration of NK cell activity and recovery from CFS. Taken together, immunological abnormalities may be involved in CFS, and its restoration may produce clinical benefit in CFS.

Abstract: BACKGROUND: No somatic treatment has been found to be effective for chronic fatigue syndrome (CFS). Antidepressant therapy is commonly used. Fluoxetine is recommended in preference to tricyclic agents because it has fewer sedative and autonomic nervous system effects. However, there have been no randomised, placebo-controlled, double-blind studies showing the effectiveness of antidepressant therapy in CFS. We have carried out such a study to assess the effect of fluoxetine in depressed and non-depressed CFS patients. METHODS: In this randomised, double-blind study, we recruited 44 patients to the depressed CFS group, and 52 to the non-depressed CFS group. In each group participants were randomly assigned to receive either fluoxetine (20 mg once daily) or placebo for 8 weeks. The effect of fluoxetine was assessed by questionnaires, self-observation lists, standard neuropsychological tests, and a motion-sensing device (Actometer), which were applied on the day treatment started and on the last day. FINDINGS: The two groups were well matched in terms of age, sex distribution, employment and marital status, and duration of CFS. There were no significant differences between the placebo and fluoxetine-treated groups in the change during the 8-week treatment period for any dimension of CFS. There was no change in subjective assessments of fatigue, severity of depression, functional impairment, sleep disturbances, neuropsychological function, cognitions, or physical activity in the depressed or the non-depressed subgroup. INTERPRETATION: Fluoxetine in a 20 mg daily dose does not have a beneficial effect on any characteristic of CFS. The lack of effect of fluoxetine on depressive symptoms in CFS suggests that processes underlying the presentation of depressive symptoms in CFS may differ from those in patients with major depressive disorder.

Abstract: OBJECTIVE: To determine whether serum levels of chlorinated hydrocarbons are elevated in patients with chronic fatigue syndrome. METHODS: Chlorinated hydrocarbon levels were measured in 22 patients with chronic fatigue syndrome (CFS) (as defined by the Centers for Disease Control [CDC]); in 17 patients with CFS symptoms whose history of exposure to toxic chemicals excluded them from the research definition of CFS; and in 34 non-CFS control subjects matched for age and sex. RESULTS: DDE (1,1-dichloro-2,2-bis (p-chlorophenyl) ethene) was detected in all serum samples at levels over 0.4 ppb. The incidence of hexachlorobenzene (HCB) contamination (> 2.0 ppb) was 45% in the CFS group, compared with 21% in the non-CFS control group (P < 0.05). The CFS group had a significantly higher total organochlorine level (15.9 ppb; SEM, 4.4) than the control group (6.3 ppb; SEM, 1.1; P < 0.05). The toxic exposure group also had a higher mean organochlorine level (13.6 ppb; SEM, 6.2) than the control group, but the difference was not statistically significant. DDE and HCB comprised more than 90% of the total organochlorines measured in each of the groups. CONCLUSION: The results suggest that recalcitrant organochlorines may have an aetiological role in CFS. There were no significant differences in serum organochlorine concentrations between CFS patients and chronic fatigue patients with a history of toxic chemical exposure. Therefore, exclusion of patients from the CDC research definition of CFS on the basis of a reported history of known exposure to toxic chemicals is not valid. The role of low-level organochlorine bioaccumulation in the development of CFS symptoms requires further investigation.

Abstract: Quantitative assessment of nervous system function is essential in characterizing the nature and extent of impairment in individuals experiencing symptoms following workplace exposure. In recent years, the application of standardized neuropsychological tests to the evaluation of exposure to toxic industrial substances has significantly increased the understanding of the effects of these compounds. Within this review, the specific toxic neuropsychological effects of lead, carbon disulfide, trichloroethylene, perchloroethylene, mercury, styrene, and pesticides are discussed in detail. These discussions draw on our clinical experience with patients exposed to these substances as well as material from the medical literature. Factors affecting the utilization of these tests in occupational settings are also considered.

Abstract: The potential relationships between chlorinated hydrocarbon contamination in human serum and red/white blood cell profiles were investigated by multivariate techniques to assess the cellular response patterns to high and low organochlorine levels in the serum. Twenty-three healthy control subjects and fourteen patients with unexplained and persistent fatigue were divided on the basis of (a) high or low total organochlorine content, (b) high or low DDE (1,1-dichloro-2,2-bis(p-chlorophenyl) ethene) content, and (c) high or low HCB (hexachlorobenzene) content. Discriminant function analysis revealed that the groups with high organochlorine content had significantly different red/white blood cell profiles compared with the low organochlorine groups ((a) P < 0.017, (b) P < 0.015, and (c) P < 0.0002). As a variable, the percentage of neutrophils was the most important discriminant parameter for differentiating between the high and low total organochlorine groups. Thirteen of the fourteen fatigued patients were characterized as "high total organocholorine content" (P < 0.04). The red cell distribution width was elevated in the high DDE group (P < 0.04) and was the most important discriminant parameter for differentiating between the high and low DDE groups. The percentage of eosinophils and the hemoglobin content were both reduced in the high HCB group (P < 0.009,P < 0.003, respectively) and the percentage of eosinophils was the most important discriminant parameter for differentiating between the high and low HCB groups. Those patients with unexplained and persistent fatigue had significantly higher levels of DDE compared with the controls and had different specific blood cell responses to organochlorines compared with control subjects.

This text is a unique vehicle for researchers, physicians and other health education and government officials, and is also easily understandable by the general public. See the Review of this book for more information and for purchasing details. Dr Byron Hyde is the world's preeminent ME authority.

: BACKGROUND: Chronic Fatigue syndrome (CFS) is a relatively newly defined clinical entity that affects multiple systems including the ocular system. These effects have not been well documented. METHODS: 25 consecutive CFS patients were evaluated and the ocular signs and symptoms were described. RESULTS: Significant ocular symptoms were present in all 25 patients. The most common clinical findings were abnormalities of the preocular tear film and ocular surface (19 patients) and reduced accommodation for age (18 patients). CONCLUSIONS: CFS affects the ocular system in many ways. Eye care practitioners should pay particular attention to accommodative needs, ocular surface disease and tear film dysfunction when examining these patients. Further research into the pathophysiology of these ocular findings may lead to a better understanding of the pathophysiology of CFS.

: The most consistent deficit observed in individuals with Chronic Fatigue Syndrome has been in efficiency of information processing. To examine the possibility of a modality-specific impairment, the present study examined subjects with Chronic Fatigue Syndrome, multiple sclerosis, and healthy controls on an auditory-versus visual-paced serial-addition test. 20 subjects with Chronic Fatigue Syndrome, 20 subjects with clinically definite Multiple Sclerosis, and 20 sedentary healthy controls were compared. One-half of the subjects in each group were administered the Paced Auditory Serial Addition Test and the other half were administered the Paced Visual Serial Addition Test. The group with Chronic Fatigue Syndrome was differentially impaired on the auditory relative to the visual processing task. The group with Multiple Sclerosis was equally impaired on both versions of the task. The results are discussed within the framework of Baddeley's model of working memory.

: Chronic fatigue and immune dysfunction syndrome (CFIDS) is a disease presenting with systemic, sensory, cognitive, and psychological manifestations. Ocular symptomatology is reported in the visual, functional, perceptual, and pathological aspects of the visual system. The purpose of the research was to evaluate ocular symptoms in patients with CFIDS. One hundred and ninety CFIDS patients [155 females, 35 males; mean age of 41 years (range 15 to 72)] and 198 healthy controls [133 females, 65 males; mean age of 42 years (range 8 to 89)] were surveyed via written questionnaire. Evaluation of data showed statistical significance at levels ranging from 0.0001 to 0.007 for all but one symptom surveyed. It appears that the ocular symptoms of CFIDS are genuine. Further research is needed to determine the etiology and appropriate treatment of this disease.

: Chronic fatigue and immune dysfunction syndrome (CFIDS) is a disease presenting with systemic, sensory, cognitive, and psychological manifestations. Ocular symptomatology is reported in the visual, functional, perceptual, and pathological aspects of the visual system. The purpose of the research was to evaluate ocular symptoms in patients with CFIDS. One hundred and ninety CFIDS patients [155 females, 35 males; mean age of 41 years (range 15 to 72)] and 198 healthy controls [133 females, 65 males; mean age of 42 years (range 8 to 89)] were surveyed via written questionnaire. Evaluation of data showed statistical significance at levels ranging from 0.0001 to 0.007 for all but one symptom surveyed. It appears that the ocular symptoms of CFIDS are genuine. Further research is needed to determine the etiology and appropriate treatment of this disease.

: Myalgic Encephalomyelitis (ME) is a form of post viral fatigue syndrome resulting in myalgia and fluctuating fatiguability. Symptoms reflecting central nervous system dysfunction are common and include muscle weakness, headache, sensory disturbances, poor short term memory and impairment of concentration. In view of the fact that sensory and cognitive disturbances are experienced by many patients objective evidence was sought with multi-modality sensory evoked potentials and auditory event-related cognitive potentials in a group of ME patients both with and without the enteroviral antigen, VP1 test positive. The auditory brainstem, median nerve somatosensory and pattern reversal checkerboard visual potentials were normal for all 37 patients tested. In contrast to the sensory potentials significant differences in the mean latencies of the cognitive potential N2 and P3 were found. Reaction times were also significantly prolonged but the performance in terms of error was not significantly affected. No significant difference emerged in any of the parameters for the VP1 test. P3 was abnormal in latency or amplitude in 36% of the VP1 positive patients for the frequency discrimination task and 48% for the more difficult duration discrimination task. The abnormalities indicate attentional deficits in some patients and slower speed of information processing in others. The prolonged latencies observed in these patients have not been observed in patients with depression in many other studies.

Chronic fatigue syndrome (CFS) is distinguished by the new onset of debilitating fatigue that lasts at least 6 months, concomitant with other symptoms to be described later. Many CFS patients complain of disequilibrium, yet the exact type of the balance dysfunction and its function and its location (peripheral vs. central) have not been described. Herein we report results of vestibular function testing performed on 11 CFS patients. These results revealed no predominant pattern of abnormalities. Patients typically performed below average in dynamic posturography testing, with a significant number of falls in the tests requiring subjects to depend heavily on the vestibular system. One patient had abnormal caloric testing, while 3 had abnormally low earth vertical axis rotation (EVA) gains at the higher frequencies tested. As a group, the average gain of EVA was significantly lower than normals in the 0.1 - 1.0 Hz range (p < 0.05). In earth horizontal axis rotation, the CFS group had a higher than normal bias value for the optokinetic (OKN) and eyes open in the dark conditions (p < 0.05), but had normal scores during visual vestibular reflex testing. Five of the 11 subjects had an abnormal OKN bias build up over the course of the run, equal to or actually exceeding the 60 degrees/s target velocity by as much as 14 degrees/s. Altogether, these results are more suggestive of central nervous system deficits than of peripheral vestibular disfunction.

Acute vestibular dysfunction and motion sickness are characterized by autonomic effects such as pallor, nausea, and vomiting. Previous anatomic and physiologic studies suggest that one potential mediator of these effects may be light, direct vestibular nuclear projections to the nucleus tractus solitarius and the dorsal motor nucleus of the vagus nerve. This study presents evidence for relatively dense, direct projections from the vestibular nuclei to the parabrachial nucleus. Male albino rabbits received injections of Phaseolus vulgaris leucoagglutinin into the vestibular nuclei. The tracer was visualized immunocytochemically with standard techniques. Anterogradely labeled axons were traced bilaterally from the vestibular nuclei to the parabrachial nuclear complex, where they terminated around somata in the Kolliker-Fuse nucleus, external medial parabrachial nucleus, medial parabrachial nucleus, and lateral parabrachial nucleus. Less dense terminations were observed in the ventrolateral aspect of the medullary reticular formation, the subtrigeminal nucleus, lateral tegmental field, and nucleus ambiguus. These findings have several important implications. First, they suggest that vestibular input converges directly at brain stem levels with visceral sensory input in both nucleus of the solitary tract and the parabrachial complex. Second, they suggest that vestibular input influences brain stem autonomic outflow via two parallel pathways: (1) direct, light projections to the nucleus of the solitary tract, dorsal motor nucleus of the vagus nerve, and ventrolateral medullary reticular formation; and (2) denser projection to regions of the parabrachial nucleus that project to these brain stem regions. Finally, since the parabrachial nucleus regions that receive vestibular input also project to the hypothalamus and the insular and infralimbic prefrontal cortex, the parabrachial nucleus may serve as an important relay and integrative structure for the cognitive impairment and vegetative symptoms associated with motion sickness, vestibular dysfunction, and responses to altered gravitational environments.

Because of the blood-brain and blood-labyrinthine barriers, the brain and inner ear were once thought to be immunoprivileged sites. Although these barriers provide protection from inflammatory damage to the delicate structures of the organs, both sites have since been shown to be capable of active immune responses when appropriately stimulated. In the inner ear, perisacular tissue around the endolymphatic sac hosts resident lymphocytes and serves as a site of immunosurveillance. Lymphocytes also enter the inner ear from the circulation, and in the cochlea this occurs via the spiral modiolar vein. Immune responses can protect the labyrinth from infection, but they can also cause bystander injury. Moreover, the cochlea can itself become the target of immune responses that damage hearing. Such autoimmune sensorineural hearing loss can be site specific, with the primary manifestation of the disorder being hearing loss and dysequilibrium. Some of these cases can be diagnosed by antibody or lymphocyte responses to inner ear antigens. Alternately, systemic autoimmune disorders can result in inner ear dysfunction as part of a broader spectrum of disease. Both forms of immune-mediated inner ear dysfunction may respond to immunosuppressive therapies, including steroids, cytotoxic agents, and plasmapheresis.

1. To study the properties of vestibulosympathetic reflexes we recorded outflow from the splanchnic nerve during natural vestibular stimulation in multiple vertical planes in decerebrate cats. Most of the animals were cerebellectomized, although some responses were recorded in cerebellum-intact preparations. Vestibular stimulation was produced by rotating the head in animals whose upper cervical dorsal roots were transected to remove inputs from neck receptors; a baroreceptor denervation and vagotomy were also performed to remove visceral inputs. 2. The plane of head rotation that produced maximal modulation of splanchnic nerve activity (response vector orientation) was measured at 0.2-0.5 Hz. The dynamics of the response were then studied with sinusoidal (0.05- to 1-Hz) stimuli aligned with this orientation. 3. Typically, maximal modulation of splanchnic nerve outflow was elicited by head rotations in a plane near pitch; nose-up rotations produced increased outflow and nose-down rotations reduced nerve discharges. The gains of the responses remained relatively constant across stimulus frequencies and the phases were consistently near stimulus position, like regularly firing otolith afferents. Similar response dynamics were recorded in cerebellectomized and cerebellum-intact animals. 4. The splanchnic nerve responses to head rotation could be abolished by microinjections of the excitotoxin kainic acid into the medial and inferior vestibular nuclei, which is concordant with the responses resulting from activation of vestibular receptors. 5. The properties fo vestibulosympathetic reflexes recorded from the splanchnic nerve support the hypothesis that the vestibular system participates in compensating for posturally related changes in blood pressure.

Vestibular influences on the autonomic nervous system. Yates BJ. Annals of the New York Academy of Science 1996; 781: 458-73.

Abstract:

Considerable evidence exists to suggest that both sympathetic and respiratory outflow from the central nervous system are influenced by the vestibular system. Otolith organs that respond to pitch rotations seem to play a predominant role in producing vestibulo-sympathetic and vestibulo-respiratory responses in cats. Because postural changes involving nose-up pitch challenge the maintenance of stable blood pressure and blood oxygenation in this species, vestibular effects on the sympathetic and respiratory systems are appropriate to participate in maintaining homeostasis during movement. Vestibular influences on respiration and circulation are mediated by a relatively small portion of the vestibular nuclear complex comprising regions in the medial and inferior vestibular nuclei just caudal to Deiters' nucleus. Vestibular signals are transmitted to sympathetic preganglionic neurons in the spinal cord through pathways that typically regulate the cardiovascular system. In contrast, vestibular effects on respiratory motoneurons are mediated in part by neural circuits that are not typically involved in the generation of breathing.

Studies using both electrical and natural stimulation have established that the vestibular system has prominent effects on sympathetic outflow and blood pressure. Preliminary evidence suggests that receptors in both otolith organs and semicircular canals are involved in producing these effects. Furthermore, vestibulosympathetic reflexes appear to be mediated by the medial vestibular nucleus and slowly conducting projections from the rostral ventrolateral medulla and caudal medullary raphe nuclei to preganglionic neurons in the thoracic spinal cord. However, many details are missing from our knowledge and understanding of the functional significance and neural substrate of vestibular influences on the sympathetic nervous system.